However, the inventors have now set themselves the object of providing a tablet for pharmaceutical formulations which can be both taken directly orally as a chewable tablet or lozenge with a slight effervescent effect and therefore pleasant fizzy feeling in the mouth and dissolved or suspended in (preferably 50-100 ml) of water, in particular in less than 2 min, with effervescence. It is in fact highly desirable to have a tablet which generates a pleasant fizzy feeling on chewing or sucking but which, if required, can be dissolved in a (very small) amount of water if the patient prefers to drink a solution. The tablets mentioned at the outset are however unsuitable for dissolution in water before being taken: the tablet according to EP-A1-525,388 has insufficient effervescent base for this purpose since up to two thirds of the effervescent components have already reacted, i.e. only a single carboxyl group of the citric acid may be free; all tablets according to the examples of WO91/04757 have dissolution times of well over 5 minutes in fresh water.
As the inventors of the present application have surprisingly found, this is due, inter alia, to three aspects of the formulation which had not been taken into account by the inventors of WO91/04757 because they were indeed concerned only with a chewable tablet or lozenge, which, according to the description, was to dissolve in water at 37.degree. C. in less than 10 minutes. The stated relevant lower limit of 30 seconds cannot be achieved with the formulation of WO91/04757.
A first reason for this is the use of a lubricant for tabletting, which is essential according to the description. Even a relatively low content of lubricant makes the individual components hydrophobic and thus contributes very substantially to poorer dissolution behaviour of the tablet in water.
A second reason is the encapsulation or coating of the particles of the active substance: the coating material penetrates into the voids during compression and thus also blocks access to the effervescent particles. The effervescent particles then react much more slowly with the water thus impeding the dissolution of the tablets.
A third reason is the use of relatively large amounts of rapidly soluble substances as fillers, such as, for example, sorbitol alone or as a mixture with a sucrose which is formulated as a tabletting assistant and in turn contains lubricant although only in small amounts.
Surprisingly, it has in fact been found that relatively rapidly soluble fillers in a tablet having a relatively low content of effervescent base (owing to any direct oral intake of the tablet, the effervescent effect must not be too great, otherwise it will be found to be unpleasant) prolong the dissolution time of the tablet. The reason for this is that, on introduction of the tablet into water, the amounts of rapidly soluble fillers, which are large in comparison with the amount of the effervescent base, very rapidly form a locally very highly concentrated solution in which the dissolution and reaction of the effervescent components and hence the disintegration of the tablet take place only slowly.
On the other hand, if the lubricant and/or the encapsulation of the active substance are omitted, an unpleasantly strong effervescent effect may be achieved in the mouth if the tablet is to be chewed or sucked, even with small amounts of effervescent components which are required for the dissolution of the tablet in fresh water.
Attempts to achieve the object described at the outset by means of a disintegrating effervescent material doped with a small amount of effervescent base, for example according to EP-A1-501,985, also failed since the disintegrating agents always left behind a sandy, rough impression during chewing or sucking, which was found to be unpleasant.
The inventors have demonstrated this on the basis of the examples and have solved the stated problems as described herein and in the appended claims such as by formulating a tablet with an effervescent action comprising a pharmaceutically active substance, acid particles, and/or carbonate particles of an effervescent base that are coated with a soluble hydrocolloid that is preferably slightly or rapidly soluble, and/or wherein the pharmaceutical substance is free of encapsulating substances and/or the tablet mixture is free of lubricants. Advantageous further developments and alternatives of the invention are described as described herein and in the appended claims.
The small amounts of water in the saliva, in which indeed other substances are also dissolved, do not dissolve a hydrocolloid coat on the effervescent components so rapidly that an undesirably strong effervescent action would occur. Even small amounts of the hydrocolloid thus slow down the reaction of the effervescent components with one another in the mouth quite dramatically, while the hydrocolloid--in particular an essentially readily soluble one, such as, for example, maltodextrin, polyvinylpyrrolidone or guar gum--dissolves in the water very rapidly and prolongs the dissolution time of the tablet only to an insignificant extent.